The key strength of positron emission tomography (PET) is its sensitivity that permits imaging of radiotracers in the sub-nanomolar concentration range. However, less than 1% of the available signal is captured, because only a small axial segment of the body (typically 15-20 cm) is imaged at any one time. This leads to relatively long imaging times and non-negligible radiation doses, which are major limiting factors in the broader application of PET. We have assembled a consortium to develop EXPLORER, the world's first total-body scanner that allows all the tissues and organs to be imaged simultaneously and will provide an effective sensitivity gain of at least a factor of 40 over current clinical PET/CT scanners. This sensitivity gain could be used to acquire 40-fold more signal (a >6-fold increase in signal-to-noise), or to acquire total-body images in 1/40th of the time or at 1/40th of the radiation dose, or to track biomolecules over 7-9 radionuclide half-lives (~16 hours for F-18 tracers, ~30 days for Zr-89 tracers) . This has profoundly transformative implications for the application of PET in both clinical diagnostics and research, for example, (1) the ability to acquire FDG whole- body studies in 15-30 seconds (breathhold-PET), (2) the ability to perform whole-body studies in dose- sensitive applications (e.g. pediatrics, adolescents, longitudinal studies of chronic disease and longitudinal studies of cell trafficking) at doses similar to those received on a round-trip transatlantic flight, and (3) the ability to do rapid kinetic studies and obtain pharmacokinetic data from all organs simultaneously as well as an image-derived input function, facilitating new drug discovery, studies of multi-organ interactions and systems biology. With previous NIH funding we have developed all the necessary building blocks for this scanner, including innovative detectors with time-of-flight and depth-encoding capability (essential for dealing with the parallax problems arising from recording highly oblique data), electronics, a complete in silico simulation of the scanner, and image reconstruction code. In this proposal, we seek to use the knowledge we have gained to build the first total-body PET scanner. The engineering work will be guided by industry leaders, and in parallel, our medical advisory board will ensure the proposed development is consistent with the performance needs for applications across a broad spectrum of disease states. The scanner will be sited at one of four top locations (U Penn, MSKCC, UC Davis or UCSF) that have the infrastructure to take advantage of the transformative opportunity presented by this unprecedented device.